Impact of intensified prevention measures on rates of hospital-acquired bloodstream infection in medical-surgical intensive care units, Israel, 2011 to 2019

Background Central line-associated bloodstream infection (CLABSI) is among the most common preventable infectious complications in patients in intensive care units (ICU). In 2011, the Israel National Center for Infection Control initiated a nationwide CLABSI prevention programme. Aim To evaluate the impact of different components of the programme on CLABSI and non-CLABSI rates in medical-surgical ICUs. Methods We included data collected from all 29 medical-surgical ICUs in Israel from November 2011 to December 2019. The study period was divided into three phases: I (baseline, initial CLABSI prevention guidelines introduced, initial feedback on rates provided), II (initial guidelines widely implemented, surveillance undertaken, feedback continued) and III (after implementation of additional prevention measures). Interrupted time series analysis was used to compare CLABSI and non-CLABSI rates during the three phases. Results The pooled mean (SD) incidence of CLABSI per 1,000 central line-days dropped from 7.4 (0.38) in phase I to 2.1 (0.13) in phase III (p < 0.001). The incidence rate ratio (IRR) was 0.63 (95% CI: 0.51–0.79) between phases I and II, and 0.78 (95% CI: 0.59–1.02) between phases II and III. The pooled mean (SD) incidence of non-CLABSI per 1,000 patient-days declined from 5.3 (0.24) in phase I to 3.4 (0.13) in phase III (p < 0.001). Conclusion National CLABSI prevention guidelines, surveillance and feedback resulted in significant reductions in CLABSI and non-CLABSI rates. In the wake of further interventions, significant reduction was achieved in ICUs reporting improvement in the uptake of additional prevention measures.


Introduction
Hospital-acquired bloodstream infections (HA-BSI) are among the most common infections acquired by patients in intensive care units (ICUs), affecting ca 5-7% of patients admitted to ICUs [1,2]. Risk factors for HA-BSI include severeness of illness at admission, prolonged length of stay, immunosuppression and the presence of central venous catheters [2]. Hospitalacquired bloodstream infections are associated with high mortality rates, increased length of ICU stay and healthcare-related costs [3]. Findings from surveillance conducted by the World Health Organization indicate high rates of antibiotic resistance among pathogens causing bloodstream infections (BSI) [4], which may contribute to adverse patient outcomes. Bloodstream infections caused by drug-resistant pathogens are associated with higher rates of 1-year mortality compared with BSI caused by susceptible pathogens [5].
Hospital-acquired bloodstream infections may be primary or secondary to the dissemination of pathogens from another anatomic site. Primary BSI are laboratory-confirmed BSI that are not related to infection at another body site [6]. In the presence of a central venous line, primary BSI are defined as central lineassociated bloodstream infections (CLABSI). In a large European survey, 39.5% of bloodstream infections were central venous catheter-related [7]. The most common sources of secondary HA-BSI are respiratory and urinary tracts [8].
During the past 15 years, numerous national and regional programmes have focused on prevention of CLABSI. Prevention bundles, such as those first proposed by Pronovost et al. in 2006 [9], have become the standard of care for CLABSI prevention. Several multifaceted interventions subsequently conducted worldwide have resulted in a marked reduction in CLABSI rates [10].
The Israel National Center for Infection Control (NCIC) initiated a nationwide CLABSI prevention programme in 2011. The primary aim of this study is to evaluate the impact of different components of the programme on the incidence of CLABSI. Secondary aims are to determine the impact of the intervention programme on rates of non-CLABSI and total ICU-acquired BSI and to evaluate factors associated with improvement.

Design and setting
This was a prospective, non-randomised nation-wide intervention. The setting was general ICUs in all 29 of Israel's acute care hospitals, which were divided into three categories: tertiary care, medium-sized nontertiary care (≥ 400 beds) and small non-tertiary care (< 400 beds).
The study consisted of three phases: (i) phase I, baseline, upon introduction of initial prevention measures (November 2011-December 2012); (ii) phase II, after initial measures were widely implemented, surveillance undertaken and routine feedback provided to hospitals (January 2013-December 2017); (iii) phase III, after hospitals had adopted additional prevention measures (January 2018-December 2019) ( Figure 1).

Intervention I
Central line-associated bloodstream infection prevention guidelines were distributed to acute care hospitals in May 2011. In November 2011, mandatory, confidential national surveillance of HA-BSI and CLABSI was initiated. In addition, workshops for infection control and ICU staff were conducted by the NCIC throughout the intervention period. Biannual feedback on infection rates were send to hospital management and local infection control teams starting in August 2012.

Intervention II
During 2017, in response to a plateau in CLABSI rates, the following additional steps were implemented: (i) a target of achieving below the 25th percentile of the 2016 incidence rate was set; (ii) frequency of feedback was increased to quarterly; (iii) site visits were conducted by NCIC staff, during which local strategies were evaluated with infection control and ICU teams. Additional interventional elements included the following: (  (education, audits and ward champions) [11]. A follow-up survey was sent in June 2018. Each hospital received feedback with the summary of local implemented measures compared with other facilities and correlated with CLABSI incidence.

Surveillance
National BSI surveillance was launched in November 2011 using the United States (US) Centers for Disease Control and Prevention (CDC) surveillance definitions and methodologies, which were updated annually [6]. Trained infection preventionists in each facility collected data on ICU patients. From November 2011 to December 2015, hospitals reported aggregate data monthly. Intensive care unit-acquired BSI cases were classified as CLABSI or non-CLABSI, where non-CLABSI referred to cases not associated with a central line. As of May 2016, patient-level data replaced aggregate reports.
The data included all positive blood cultures, admission and discharge dates, symptoms and signs, dates of diagnostic procedures and presence of central venous lines. All positive blood cultures were classified into three categories: (i) contamination, (ii) present on admission and (iii) HA-BSI. Hospital-acquired bloodstream infections were further classified as CLABSI, primary non-CLABSI or secondary BSI. All reports were reviewed and validated by an infection preventionist at the NCIC, to ensure that the cases were classified in accordance with CDC definitions. Whenever a discrepancy was found between an institution's surveillance assessment and a CDC definition, the case was clarified with the hospital infection control team.
Total HA-BSI and CLABSI incidence rates were calculated as the number of infections per 1,000 patient-days and 1,000 line-days, respectively. Device utilisation was defined as the ratio of total central line-days to total patient-days.

Statistical analysis
Using the aggregate data collected since 2011, trends in CLABSI and non-CLABSI rates were compared between the three phases. We conducted an interrupted time series analysis to estimate the effect of the two rounds of interventions on CLABSI incidence rates. The number of cases prevented was estimated by comparing the expected number of CLABSI events based on the 2012 rate to the observed number in years 2013-2019.
Using the expanded patient-level data collected since mid-2016, which allowed us to verify hospitals' classification of BSI as CLABSI or non-CLABSI and to assess the sources of non-CLABSI events, we compared the incidence rates between two periods: (i) period 1, before the adoption of additional prevention measures (May 2016-December 2017); and (ii) period 2, after the adoption of additional prevention measures (January 2018-December 2019).

What did you want to address in this study?
During the past 15 years, national and regional interventions have reportedly led to a marked reduction in central line-associated bloodstream infections (CLABSI), yet sparse data exist on the impact on total hospital-acquired BSI (HA-BSI). We assessed the impact of different components of a national programme on the incidence of CLABSI and total HA-BSI in intensive care units in Israel.
What have we learnt from this study? Over 8 years, a national intervention conducted in Israeli ICUs prevented ca 2,200 episodes of HA-BSI, including 1,300 CLABSI events. The reduction in CLABSI rates was observed in two stages. An initial reduction occurred shortly after implementation of prevention bundles, infection surveillance and feedback. Following introduction of additional measures, a further reduction was observed.

What are the implications of your findings for public health?
The rate of total HA-BSI may be a more objective measure of hospital safety than CLABSI rates alone. Furthermore, CLABSI events account for only 25-35% of all HA-BSI. National surveillance programmes should thus monitor additional causes of preventable HA-BSI. Assessment of prevention measures may uncover the reasons for variation in infection rates between facilities and reveal gaps in knowledge and resources.

KEY PUBLIC HEALTH MESSAGE
aeruginosa and Acinetobacter spp.); (iii) Gram-positive bacteria (Enterococcus spp., Staphylococcus aureus, coagulase-negative staphylococci); and (iv) Candida spp. All pathogens not included in the prior four categories were grouped as 'other'. The pooled mean pathogen-specific incidence per 10,000 patient-days was calculated for primary (CLABSI and non-CLABSI) and secondary BSI events. Incidence rate difference (IRD) between periods was calculated.
For each round of surveys, hospitals were assigned a prevention score based on the number of CLABSI prevention measures that they had implemented. The association between the prevention score and CLABSI rates during the first and second surveys was assessed using Spearman's correlation. Student's t-tests were used to compare uptake of prevention measures at baseline and follow-up. Hospitals were categorised into two groups based on high (> median score on the first survey) or low (≤ median score on the first survey) uptake of prevention measures. Incidence rate ratio (IRR) was used to compare CLABSI rates between periods 1 and 2 separately for hospitals with high and low uptake of prevention measures at baseline. Significance was set at p < 0.05. Data were analysed using Python version 3.7.4 (Python Software Foundation, Wilmington, US) and Rstudio version 3.6.3 (Posit Software, Boston, US).

Central line-associated bloodstream infection and non-central line-associated bloodstream infection rates
The Table summarises CLABSI and non-CLABSI incidence rates and central venous catheter use by year. As shown in Figure 2, the mean (standard deviation (SD)) pooled monthly incidence of CLABSI per 1,000 central line-days dropped from 7.4 (0.38) in phase I, to 3.8 (0.11) in phase II, to 2.1 (0.13) in phase III (p < 0.001 for phase I vs phase III). Incidence rate ratio was 0.63 (95% CI: 0.51-0.79) between phases I and II, and 0.78 (95% CI: 0.59-1.02) between phases II and III.

Comparison of uptake of prevention measures and association with central line-associated bloodstream infection rates
Twenty-one of 29 acute care hospitals completed both surveys. Figure 5 illustrates the uptake of different prevention measures in the two survey rounds. The most widely used prevention measures were dedicated supply carts for central line insertion, routine chlorhexidine (CHD) bathing and CHD-impregnated dressings at the insertion site. The greatest increase between the surveys was found for performing simulation training and use of alcohol caps. Fewer than half of the facilities reported routine use of ultrasound during central line insertion or conducting audits on insertion and maintenance practices.
The mean (SD) number of prevention measures increased from 7.3 (2.9) in the baseline survey to 9.9 (2.0) in the follow-up survey (p = 0.002). In the first period, the pooled CLABSI incidence rate was higher in the 14 ICUs with low prevention scores (4.4 per 1,000 line-days) than in the seven ICUs with high prevention scores (2.9 per 1,000 central line-days) (IRR: 1.5, 95% CI: 1.2-2.0, p < 0.001). In the group of hospitals with low prevention scores at baseline, the mean number of prevention measures used increased from 6.0 at baseline to 9.9 at follow-up (p < 0.001), and the pooled CLABSI incidence rate in this group decreased from 4.4 to 1.9 per 1,000 line-days (IRR: 0.44, 95% CI: 0.32-0.59, p < 0.001). In hospitals with high prevention scores at baseline, neither the mean score (10 vs 9.8) nor the pooled CLABSI rate (2.9 vs 2.3) changed significantly between the two periods.

Discussion
During a period of 8 years, a national intervention conducted in medical-surgical ICUs in Israel achieved a significant and sustained reduction in both CLABSI and non-CLABSI rates. The reduction in CLABSI rates was observed in two stages. The first reduction occurred shortly after widespread implementation of a national evidence-based prevention bundle, infection surveillance and feedback. Subsequently, during a period of 5 years, no significant change was observed in CLABSI rates. In 2018, following a multifaceted intervention, a further reduction was observed. The reduction in CLABSI rates was likely achieved by the multimodal intervention approach taken, which included feedback to hospitals on adoption of prevention measures in comparison with other hospitals and the inclusion of CLABSI rates in a nationwide incentive programme and public reporting. Of note, a significant reduction was achieved only in ICUs reporting improvement in the uptake of additional prevention measures. Additionally, although the national programme was initially focused on CLABSI-targeted interventions, the continuous measurement and feedback on all cases of HA-BSI led to a progressive and sustained reduction in non-CLABSI rates.

The seminal 1988 Study on the Efficacy of Nosocomial
Infection Control (SENIC) demonstrated that surveillance is a fundamental tool for preventing hospital-acquired infections [12]. Since the SENIC study, implementation of national surveillance systems has led to a marked reduction in CLABSI rates [13][14][15]. Nevertheless, CLABSI rates may remain high despite implementation of surveillance programmes [16]. Variability in the use of prevention measures, failure to assess compliance and insufficient involvement of hospital management all likely contribute to suboptimal outcomes [17]. Central line-associated bloodstream infection rates in resource-limited countries are 3-5 times higher than those in high-income settings [14,18]. Lower compliance with insertion and maintenance prevention measures was reported in middle-income countries compared with high-income countries [19].
National assessment of prevention measures may uncover the reasons for variation in infection rates between facilities and reveal gaps in knowledge or resources. In our previous study, we found an association between a high prevention score and low CLABSI rates [11]. Tertiary hospitals, where CLABSI rates were lowest, reported greater use of prevention measures compared with other hospital categories. High infection rates in smaller hospitals may reflect the lack of infection control personnel and resources [14].
The follow-up assessment revealed an increase in uptake of prevention measures and an accompanying decrease in CLABSI rates. This increase was observed in facilities with low prevention scores in the first assessment. Most hospitals have implemented the use of certain technology measures (e.g. insertion cart or CHD dressing). However, other prevention tools, such as simulation training and line-care audits, were adopted to a lesser extent. Hands-on training through simulation was found to be more effective than traditional education for teaching sterile technique and ultrasound skills [20]. In addition, high compliance with insertion and maintenance bundles was found to be associated with low CLABSI rates [21]. Future regional and national interventions should incorporate simulation training and routine measurement of compliance with the bundle elements.
Central line-associated bloodstream infection rates are increasingly published in US healthcare facilities and the data are available to consumers, healthcare providers and hospital administrators and enable comparisons of hospital performance [22]. However, poor inter-rater agreement in classifying infection events makes it difficult to reliably compare rates at different facilities [23]. Furthermore, underestimation of true CLABSI incidence has been found in publicly reported data, diminishing the validity of surveillance measures [24]. Thus, national surveillance programmes should incorporate regular external validation methods to ensure the accuracy of the reported data. One of the strengths of our surveillance programme is that all positive blood cultures are reported and validated. We therefore believe that the decrease in HA-BSI events we found is real and not an artefact of misclassification or under-reporting.
Total hospital-acquired BSIs may be a more objective measure of hospital safety than CLABSI, as there is no classification involved. In 2011, to avoid misclassification of CLABSI events, Israel mandated reporting of all HA-BSI. In all the study years, CLABSI accounted for only 25-35% of all HA-BSI, indicating that national surveillance programmes should include additional sources of preventable HA-BSI. Notably, during the study period, in addition to a decrease in CLABSI rates, we observed a persistent decrease in non-CLABSI events. The significant decrease in non-CLABSI rates was not related to the timing of targeted CLABSI control measures but may be attributable to other concurrent interventions. For example, throughout the study period there was intense national activity directed towards reducing hospital-acquired infections, including catheter-associated urinary tract infections and prevention of carbapenem-resistant Enterobacterales infection and colonisation [25]. Classification of non-CLABSI events is essential to identify intervention targets. Since 2016, the individualised reporting system enabled us to review all positive BSI classifications including contaminants, secondary and primary BSI events. Most HA-BSI events were associated with medical devices, including ventilators and central venous catheters. Intensified interventions to reduce ventilation days and urinary catheter use can be expected to have further impact on HA-BSI.
In the current study, Gram-negative bacteria were found to comprise a sizable proportion of primary BSI, accounting for ca 39.0% (413/1,059) of cases. Gram-positive bacteria were involved in only 26.4% (280/1,059) of events. During recent years, Gramnegative bacilli and Candida spp. have become leading causes of primary BSI [26,27]. In our study, most pathogen-specific CLABSI rates decreased over time, with the exception of Candida spp. Central line insertion and maintenance bundles may be less effective at preventing bloodstream infections caused by Candida. Current CDC definitions, however, may also influence pathogen distribution. Candida spp. are not eligible to be considered causative of urinary tract infection or pneumonia [6]. Consequently, most candidaemia events will be defined as primary BSI. Understanding trends in pathogen epidemiology may help in the development of prevention measures tailored to specific pathogens.
The strengths of this study are that it is at country level, and that, since May 2016, all the reported data have been validated. The study has a number of limitations. It was an observational study, lacking a control group. Therefore, it is difficult to determine whether there are factors other than the intervention that contributed to the reduction in CLABSI and HA-BSI rates. Furthermore, implementation of prevention measures was assessed using questionnaires rather than direct observations in each facility. An additional limitation is that the frequency of blood culture collection may have an impact on the incidence of HA-BSI [28]. We did not collect data on the monthly rate of blood cultures obtained in each unit. The study lacks demographic characteristics of the patients. However, individual risk factors have been demonstrated to be less important than infection control practices in determining CLABSI rates. For example, following the implementation of enhanced care bundles, a sustained decrease in CLABSI rates was achieved despite a continuous increase in underlying disease severity over time [29]. Finally, while division of the study period into discreet phases based on timing of policy initiatives is necessary for purposes of analysis, actual implementation of policy changes across multiple institutions occurs gradually and at varying paces based on the respective hospital. Therefore, the true, ultimate effect of our intervention on BSI events prevented may be greater than that reflected in the statistical analysis.

Conclusion
We found significant reductions in CLABSI and non-CLABSI rates over a period of 8 years in the context of a national intervention, associated with implementation of specific prevention measures at different points in time. A large proportion of the non-CLABSI events were associated with invasive devices and may be preventable.